Glucagon-like Peptide-1 (GLP-1) is derived from the transcription product of the proglucagon gene, which in humans is known to be expressed in the pancreas and small intestine. Expression of proglugagon in pancreatic a cells results in the 29-amino acid glucagon peptide, glucagon related pancreatic peptide (GRPP), and the major proglucagon fragment. However, in intestinal endocrine cells, glucagon related pancreatic peptide (GRPP), oxyntomodulin, GLP-1, and GLP-2 are synthesized from the proglucagon gene. The 30-amino acid endogenous GLP-1 peptide belongs to the incretin family of hormones, and plays multiple roles in metabolic homeostasis following nutrient absorption. The major source of GLP-1 in the body is the intestinal L-cell, which secretes GLP-1 as a gut hormone in response to nutrient ingestion. GLP-1 secretion by L-cells is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues of this hormone include major nutrients such as carbohydrate, protein and lipid. The biologically active forms of GLP-1 are GLP-1(7-37) and GLP-1(7-36)amide. The biological activities of GLP-1 include inhibition of glucagon secretion from the pancreas, gastric emptying, and inhibition of food intake by increasing satiety. In particular, GLP-1 has modulating effects on insulin release. GLP-1 receptor stimulation enhances insulin biosynthesis, beta-cell proliferation, glucose-dependent insulin secretion from the pancreas, and lowers blood glucose in patients with type-2 diabetes mellitus (Gault et al., 2003). The finding that GLP-1 lowers blood glucose in patients with diabetes, taken together with suggestions that GLP-1 may restore beta-cell sensitivity to exogenous secretagogues, suggests that augmenting GLP-1 signalling is a useful strategy for treatment of diabetic patients.
Neuroplasticity is a process that involves the continual formation of new neural connections, and which occurs during the (re-)organisation of the brain in response to activity and experience. Activity-dependent synaptic plasticity plays a vital role in sculpting synaptic connections during development. However, although well known to occur during development, the process is also a central feature of the adult brain. The plastic nature of neuronal connections allows the brain to continually develop in response to experience, and to circumvent the impaired neuronal signalling that occurs as a consequence of trauma or damage to neurons.
There are two types of modifications that are thought to occur in the brain during this process: 1) morphological changes to the neurons themselves, specifically in the area of the synapse; and 2) an increase in the number of synapses between neurons. The efficiency of synaptic signalling is often dependent on either (or both) of these modifications. Indeed, it is widely accepted that processes such as memory formation and learning ability are dependent on alterations in synaptic efficiency that permit strengthening of associations between neurons. Moreover, synaptic plasticity at certain synapses is thought to be both necessary and sufficient for the process of storing information in the brain.
Long-term potentiation (LTP) has long been proposed as a model for the mechanism by which the strengthening of synaptic connections can be achieved. It has been widely demonstrated that high-frequency stimulation can cause a sustained increase in efficiency of synaptic transmission. Based on this finding, it is believed that the synaptic changes that underpin at least certain forms of learning and memory are similar to those changes required for expression of LTP.
Furthermore, it is widely accepted that impaired LTP is often associated with impaired cognitive function. In this regard, for a number of years now, studies have reported cognitive deficits in aged rats. In particular, aged rats have been shown to exhibit deficits in spatial information processing. Correlated with deficits in performance in spatial learning, was a deficit in LTP in the CA1 region of the rodent brain; wherein severely impaired animals did not sustain LTP, whilst sustained LTP was observed in those animals that were relatively unimpaired in spatial learning.
Therefore, cognitive deficits are a hallmark of a number of neurological disorders. For example, the symptoms of age-related memory impairment are often similar to those symptoms associated with the early stages of neurodegenerative diseases such as Alzheimer's disease. Clearly, a major goal in the field of neuroscience is to sustain LTP in circumstances where LTP is impaired, either by age, disease-associated causes, or by any other instance resulting in impaired synaptic transmission.
However, there is growing evidence that mature neurons may also possess mechanisms to prevent the strengthening of input synapses. Such homeostatic regulation ensures that a neuron operates within an optimal activity range, a process that is integral to maintaining the highly plastic nature of the brain. This is evident in the hippocampus, where pyramidal cells of the CA1 region each receive thousands of excitatory inputs with the potential for activity-dependent enhancement of synaptic transmission. In the absence of a mechanism to limit synaptic strengthening, the physiological balance can be compromised, resulting in the LTP process being shut down, and ultimately leading to a reduced capacity of the entire neuronal circuit for storing information. Therefore, the process of depotentiation also acts as a critical mediator in regulating neuronal homeostasis and ensuring the coordinated control of the strength of synaptic transmission. Depotentiation is now thought to play a role in the removal of redundant information from the memory. As such, depotentiation could act as a potential therapeutic measure in disorders associated with overactive cognitive processes.
It is an object of the present invention to prophylactically prevent, improve, or reverse the diminished cognitive function associated with these types of disorders, by increasing (or sustaining) the LTP of synaptic transmission. Moreover, sustaining LTP may find utility in the prophylaxis of neurological disease by delaying the onset of impaired cognitive processes, and could serve as a treatment, not only for the diminished cognitive function caused by neurodegeneration, but also for the dysfunctional cognitive processes associated with trauma or age.